Down syndrome (DS) usually caused by chromosome 21 trisomy and is a major cause of mental retardation and congenital heart (CHD) and gut disease affecting over 200,000 persons in the United States alone. The characteristic heart abnormalities in DS-CHD include atrioventricular canal and ventricular septal defects. Other features of DS include a set of characteristic facies, thymic abnormalities, increased risk of leukemia and early onset of Alzheimer-like dementia. Molecular analysis of rare patients with DS and partial chromosome 21 duplications and monosomies has led to the association of certain chromosomal regions with specific DS phenotypes (Korenberg et al., Proc. Natl. Acad. Sci. USA M91:4997-5001 (1994); Delebar et al., Eur. J. Human. Genet. 1:114-124 (1993); Antonarakis et al., Progress in Clinical and Biological Research 311:29-43 (1989)). Chromosome 21 is therefore a model for the study of human chromosomal aneuploidy and the construction of its physical map is of special interest.
Human chromosome 21 has a nearly complete physical map with a well characterized contiguous set of overlapping YACs spanning most of its length (Chumakov et al., Nature 359:380-387 (1992); Shimizu et al., Cytogenet. Cell Genet. 70:147-182 (1995); Korenberg et al., Genome Research 5:427-443 (1995)). The demand for sequence ready contigs and clones for gene isolation efforts has prompted the construction of numerous higher resolution contigs in cosmids (Patil et al., Hum. Molec. Genet. 3:1811-1817 (1995)) and more recently in PACs (Osoegawa et al., Genomics 32:375-387 (1996)). Considerable mapping efforts exist in the region from CBR to D21S55 due to the duplication of this region in partially trisomic individuals with several phenotypic features of DS including mental retardation. However, the distal and adjacent, 4-5 Mb D21S55 to MX1 region is also of interest due to its association with Down syndrome congenital heart disease (DS-CHD) as well as other characteristic features of DS (Korenberg et al., Am. J. Hum. Genet. 50:294-302 (1992), Korenberg et al. (1994)). Although non-chimeric YACs span this interval, three are not as yet any higher resolution physical maps are available for the entire D21S55 to MX1 region. Thus, higher resolution physical maps for the entire D21S55 to MX1 region are desired. In addition, there is a need in the art for an isolated nucleic acid, and isolated protein encoded thereby, associated with congenital heart disease (CHD).